3-oxo-5alpha, 10alpha-dihydroxyestrane compounds



United States Patent 3,374,229 S-OXO-Sa,Illa-DIHYDROXYESTRANE COMPOUNDSKanzo Sasaki, Osaka-shi, Japan, assignor to Shionogi &

Co., Ltd., Osaka, Japan N0 Drawing. Filed Dec. 22, 1965, Ser. No.515,758 Claims priority,application Japan, Dec. 29, 1964, 39/74,388 8Claims. (Cl. 260-23955) ABSTRACT OF THE DESCLOSURE Hypocholesteremic3-oxo-5a,l0a-dihydroxyestranes are prepared by the action of an agentwhich is generally used for oz-CiS-glYCOl formation from a double bondon 3-protected-oxo-estr-5(10)-enes, followed by hydrolysis of ketalgroup.

The present inventionv relates to novel 5,10,17-trihydroxy-estranecompounds, especially to pharmaceutically useful steroidal compoundsgenerally representable as:

and R represents a hydrogen atom, a lower alkanoyl group or benzyl.

The said .3-oxo-5a,1oa-dihydroxyestrane compounds are useful, forexample, as serum lipid shifting agents valuable in the treatment ofatherosclerosis in warm-blooded animals. For example,5,l0,l7B-trihydroxy 5a,wet-estran- 3-one (subcutaneous) andl7a-methyl-5,10,17fi-trihydroxy-5ot,l0a-estran-3-one (oral) eachdecreased the total cholesterol level about 18% in plasma and 15% inratio of levels of cholestrol/phospholipids (plasma total) in a testwherein 1 mg. of each is administered to rats for 10 consecutive days.In addition it may be noted that the compounds do not inhibit thephysiologically normal biosynthesis of cholesterol and do not produceany physiologically harmful intermediates in the said cholesterolbiosynthesis route. Moreover the compounds exhibit rather slighthormonal side-effects.

The said 3-oxo-5a,lOa-dihydroxyestrane compound can be prepared from thecorresponding starting material of the formula:

wherein X represents a lower alkylenedioxy group and Y has itsabove-noted significance, by hydroxylation with a hydroxylating agent,followed by hydrolysis of the resultant product with acid.

As the said lower alkyl group in the above definition of R, a loweralkyl having 1 to 8 carbon atoms, especially methyl, ethyl, propyl,hexyl octyl or isopropyl, is preferred. As the said lower alkenyl oralkynyl group in the same R, an unsaturated group having 1 to 8 carbonatoms, especially vinyl, ethynyl, allyl, propargyl, hexenyl orisopentenyl, is preferred. As the said lower alkanoyl group in the abovedefinition of R, a lower alkanoyl group having 1 to 8 carbon atoms,esmcially formyl, acetyl, propionyl, butyryl, trimethylacetyl,tert.-butylacetyl, octanoyl or the like, is preferred. As the said loweralkylenedioxy group in the above definitions of X and Y, analkylenedioxy group having 1 to 5 carbon atoms, especiallymethylenedioxy, ethylenedioxy, propylenedioxy or the like, is preferred.

The hydroxylation, which conducts the 5(10)-double bond mainly to the5u,10a' glycol system, may be carried out by the agent which isgenerally used for cis-glycol formation from a double bond, such asosmium tetroxide, ruthenium tetroxide, potassium permanganate,iodosobenzene acetate-osmium tetroxide mixture, or the like, in theconventional manner.

The hydrolysis, which converts a 3-ketal function to free 3-ketone, maybe carried out by catalysis of acid substance, e.g. an organic acid suchas formic acid, acetic acid, propionic acid, succinic' acid, tartaricacid, malonic acid, p-toluenesulfonic acid or the like, an inorganicacid such as hydrochloric acid, sulfuric acid, perchloric acid or thelike, or an acidic salt or buffer such as potassium hydrogen sulfate,phosphate buffer or the like, in the conventional manner.

In the process, there may preferably be applied an in terconversionbetween a free function and :1 corresponding functional derivative, e.g.17,8-hydroxyl and its lower alkanoyl esters or benzyl ether, for theisolation and purification'of the reaction products more convenientlyemployed in the recovery procedure, such as extraction,recrystallization, chromatography or the like.

Further, chemical transformations may be carried out within thedefinition of Y, relative to l7-substitution, at an appropriatestageinthe process. For example, a l7B-hydroxy (17a-H) compound can beconverted to the corresponding 17-oxo compound by a conventionaloxidation with chromic acid, chromic anhydride (chromium trioxide),N-halocarbonamide or imide or by the Oppenauer oxidation before or afterthe said hydroxylating reaction; the l7-oxo compound can be converted tothe corresponding 17oc-lOW6I alkyl or alkynyl(17B -OH) compound byreaction with the corresponding Grignard reagent or lithium compound ofa lower alkane or alkyne such a methylmagnesium iodide, ethylmagnesiumiodide, butylmagnesium bromide, butyllithium, ethynyllithium,propargyllithium or the like in the conventional manner before or afterthe said hydroxylating reaction; and the said 17a-alkynyl group can behydrogenated by the conventional method using a catalyst such aspalladium, platinum or nickel, before or after the said hydroxylatingreaction.

The pharmaceutically valuable compounds of the invention may beadministered in conventional pharmaceutical formulations, such asinjections, tablets, pills, powders, etc., which can be prepared inadmixture with ordinarily used pharmaceutically acceptable carriers,excipients or the like, such as surface active agents, inorganic salts,talc, lactose, etc., to animals suffering from atherosclerosis.

Example 1.Preparation of 5,10,1 7fi-trihydr0xy-5/8J0fland-5a,10u-estran-3-0ne l) A suspension consisting of 17/8-hydroxy-5(10)-estren-S-one (I. Am. Chem. Soc., 75, 5366 (1953)) (1 part by weight) andethylene glycol (50 parts by volume) is, after addition of anhydrousbenzene (40 parts by volume), distilled azeotropica'lly to remove tracemoisture. To the mixture there is added malonic acid (0.1 part byweight) and the resultant mixture is stirred for 10 hours at roomtemperature and then let stand overnight. The reaction mixture isneutralized with aqeuous diluted sodium carbonate solution and extractedwith ether. The extract affords crude 3,3-ethylenedioxy 5(10) -estren-17fi-ol (1.2 parts by weight) on evaporation.

(2) The above-mentioned ketal compound is dissolved in anhydrous benzene(40 parts by volume). To the solution there is added a mixture of osmiumtetroxide (1.1 parts by weight) and pyridine (2 parts by volume) and theresulting mixture is then subjected to reaction at room temperature for93 hours. The reaction mixture is distilled under reduced pressure. Tothe resultant residue there are added benzene (65 parts by volume),ethanol (45 parts by volume), aqueous l%-potassium hydroxide solution(50 parts by volume) and mannitol (10 parts by weight), and theresultant mixture is refluxed for hours. The mixture is admixed withwater and separated by separating funnel to collect the organic layer.The aqueous layer is, on the other hand, extracted with ether and thenwith chloroform. The organic layer is combined with the above etheraland chloroform extracts, washed with water, dried and evaporated, thusyielding a mixture of 3,3-ethylenedioxy 55,105- and5a,100t-6Stlall6-50t,100c, 17fi-triols (0.9 part by Weight).

(3) The above triol mixture is acetylated by acetic anhydride parts byvolume) in pyridine (20 parts by volume) at room temperature for 23hours and treated thereafter in a conventional manner to afford crudecrystalline product (1 part by weight). The crude product is subjectedto thin-layer chromatography according to the above-mentioned procedure,extracted with chloroform and crystallized from ether to afford3,3-ethylenedioxy 5/3,10fl-estrane-S,10,17,8-triol 17-aceta'te, platesof M.P. 166l67.5 C. (0.4 part by weight) and3,3-ethylenediQXy-Sa,IOa-estrane-S,l0,17B-triol 17 acetate, needles ofM.P. 196196.'5 C. (0.5 part by weight).

(4) 3,3-ethylenedioxy 5B estrane-5,10,17fl triol l7- acetate (3.2 partsby weight) is dissolved in a solution of potassium hydroxide (2 parts byweight) in methanol (100 parts by volume) and the resultant mixture isrefluxed for 40 minutes. To the reaction mixture there is added Dry Iceto reduce the alkalinity from hydroxide to carbonate. The mixture isconcentrated under reduced pressure and the resultant concentrate is,after dilution with water, neutralized by, ion exchange resin (such asAmberlite IR-120; trade mark) and evaporated under reduced pressure toafford crude crystalline substance (2.8 parts by weight). The substanceis recrystallized from ether-hexane mixture to afford pure crystals of3,3- ethylenedioxy-Sfi,IO/B-estrane-S,10,17 8-triol, M.P. 173.5 175 C.

Following a similar hydroylsis procedure,3,3-ethylenedioxy-5a,IOu-estrane-S,10,17B-triol 17-acetate yields 3,3-ethylenedioxy 5a,10a estr-ane-5,10,17p-triol, M.P. 217- 222 C.

(5) 3,3-ethylenedioxy 55,105 estrane-5,=10,17 S-triol (1 part by weight)is dissolved in a mixture of ace-tic acid.

(40 parts by volume) and water (20 parts by volume).

The resultant solution is heated for 20 minutes and then evaporatedunder reduced pressure to leave the crude product (0.95 part by weight).The product is subjected to thin-layer chromatography with the solventsystem chloroform-acetone (1:1), extracted with chloroformmethanol(10:1) mixture and crystallized from dichloromethane-hexane-ethermixture to afford 5,10,17ti-trihydroxy-SB,10B-es-tran-3-one, M.P.118-'120 C. (0.5 part by weight) 3,3-ethylenedioxy 5a,10uestrane-5,'10,17/3 triol (1.5 parts by weight) is dissolved in a mixtureof acetic acid (20 parts by volume) and water (10 parts by volume). Theresultant solution is maintained at 73-75 C. for 20 minutes and thenevaporated. The resultant crude product is recrystallized from ether andacetone in order to obtain crystalline substance having M.P. -120 C.(1.2 parts by weight). Drying the substance at 60 C. for 2 hours yields3,3-ethylenedioxy-5(10)-estren-17-one (3.2 parts by estran-3-one, M.P.158l60 C.

Example 2.Preparati0n of 17 x-methyl-5,10,17B-trihydroxy-S [3,1 0,8- and-5a,10otLStlaI1-3-0Il (l) 3,3-ethylenedioxy-5(l0)-estren 17fi-ol (4.7parts by weight) is oxidized in a mixture of pyridine parts by volume)and chromium trioxide (10.7 parts by weight) for 1 hour with externalice-cooling and stirring. The reaction mixture is allowed to stand atroom temperature for 24 hours, then mixed with ice water and extractedwith ether. The extract is washed with dilute hydrochloric acid, water,aqueous dilute sodium carbonate solution, aqueous sodium chloridesolution and water, in that order and then distilled to leave crudecrystalline substance. Recrystallization of the substance fromether-hexane mixture and then from wet methanol yields3,3-et'hylenedioxy-5 l0)-estren-l7one (3.2 parts by weight), M.P.126-128 C. A chromatography over alumina of the mother liquor producesmore of the same crystalline substance (0.3 part by weight).

(2) To the methyllithium solution prepared by the reaction of lithiummetal (2 parts by weight) and methyl iodide (27.4 parts by weight) inanhydrous ether (110 parts by volume) in the presence of a small amountof iodine, a solution of 3,3ethylenedioxy-5 (10) estren-17- one (3.0parts by weight) in anhydrous benzene (60 parts by volume) is addeddropwise at room temperature. The resultant mixture is allowed to standfor 7 hours, then added to aqueous '10%-a-mmonium chloride solution withexternal ice-cooling and extracted with ether. The extract is washedwith aqueous sodium chloride solution and then distilled to leave crudeproduct (3.2 parts by weight), which is subjected to chromatography overalumina (50 parts by weight). The fraction eluted by the solvent sys-Item petroleum ether-benzene (5-1:1) gives the starting unchanged ketonecompound (0.3 part by weight), and the fraction eluted by the solventsystems benzene from benzene-ether (40-15 :1) gives3,3-ethylenedioxy-17ctmethyl-5(10)-estren-l7;3-ol (2.3 parts by weight),M.P. 114-116.5 C., after recrystallization from ether-hexane mixture.

(3) 3,3 ethylenedioxy-l7u-methyl-5(10)-estren-17}8ol (1.5 parts byweight) is dissolved in anhydrous benzene (30 parts by volume). To theresultant solution there is added osmium tetroxide (1.4 parts by weight)with external ice-cooling. The mixture is then subjected to reaction for62 hours at room temperature. A stream of hydrogen sulfide is bubbledthrough the reaction mixture, which is then filtered to removeprecipitates. The precipitates are washed with chloroform-methanol(10:1) mixture. The filtrate and washings are combined, washed withwater, dried and distilled to leave crude product (1.7 parts by weight).The crude product is subjected to thin-layer chromatography with thesolvent system chloroform-methanol (200:25) mixture. An adsorption bandin the chromatogram is extracted with chloroformmethanol mixture andrecrystallized from wet methanol to afford3,3-ethylenedioxy-17a4methyl-5p,IOB-estrane- 5,10,1713-triol (0.5 partby weight), M.P. 164-165.S C. Another band in the same chromatogramaffords 3,3- ethylenedioxy-17u-methyl-5a,10a-estrane 5,10,175 triol (0.7part by weight), M.P. 265-268 C. by extraction with chloroform-methanolmixture followed by recrystallizations using acetone andmethanol-chloroform mixture.

(4) A mixture of3,3-ethylenedioxy-17a-methyl5fl,10pestrane-5,lO,17}3-tri0l (3.5 parts byweight), acetic acid (100 parts by volume) and water (30 parts byvolume) is heated to around 80 C. for 15 minutes and evaporated underreduced pressure to leave crude crystalline product (3.1 parts byweight). The crude product is subjected to thin-layer chromatographywith the solvent system chloroform-methanol (:1), extracted withchloroformmethanol (10:1) and recrystallized from acetone-hexane mixtureto yield 17u-methyl-5,l0,17;8-trihydroxy-5;8,10B- estran-3-one (2.5parts by weight), M.P. l81182 C.

3,3-ethylenedioxy-17u-methyl-5a,10u-estrane 5,10,1713- triolcorrespondingly produces17a-methyl-5,10,17;3-trihydroxy-Sa,10a-estran-3-one, M.P. 202-210 C. byhydrolysis with acetic acid followed by recrystallization from wetmethanol.

(1) 3,3-ethylenedioxy-5(10)-estren-17B-ol (4 parts by Weight) isdissolved in a mixture of pyridine (40 parts by volume) and acetic acid(40 parts by volume), the resultant solution is warmed on a water bathfor 1 hour and thereafter treated in a conventional manner. The crudeproduct thereby obtained is chromatographed over alumina to afford3,3-ethylenedioxy-5(10)-estren-17fl-ol acetate (3.3 parts by weight),M.P. 102-103 C.

(2) 3,3-ethylenedioxy-5(10)-estren-l7 3-ol acetate (1 part by weight) isoxidized by osmium tetroxide and decomposed lby mannitol, in thesirnilar manner to the above Example 1 2), to aiford a mixture of 3,3-ethylenedioxy-5fl,10/3- and -5ot,10a-estrane-5,10,17fi-triols (0.7 partby weight).

(3) The above-prepared triol mixture (0.7 part by weight) ischromatographed over alumina (280 parts by weight). The fraction elutedwith benzene-chloroform (10-1: 1) system affords3,3-ethylenedioxy-5fl,10,8-estrane- 5,10,17fi-triol, M.P. 173.5175 C.(0.4 part by weight) after recrystallization from ether-hexane mixture.The fraction eluted with chlorofonrmmethanol (10:1) system affords3,3-ethylenedioxy-5a,IOa-estrane 5,10,17,8 triol, M.P. 217-222 C. (0.2part by weight) after sequential recrystallizations with ether-hexaneand 'dichloromethanehexane.

(4) 3,3-ethylenedioxy-5 18,1013 estrane 5,10,17/3 triol 3.1 parts byweight) is dissolved in a mixture of pyridine (20 parts by volume) andacetic anhydride parts by volume) and the resulting mixture is heatedfor 1 hour on a water bath. The reaction mixture is evaporated underreduced pressure. The residue is azeotropically distilled by addition ofhexane to remove acetic anhydride and then recrystallized fromacetone-hexane mixture, thereby yielding the corresponding 17-acetate,M.P. 166-1675 C. (3.4 parts by weight).

3,3-ethylenedioxy-5a,10u estrane 5 ,10,17{3 triol (1.4 parts by weight)is acctylated-and treated similarly and recrystallized fromacetone-hexane, thereby yielding the corresponding 17-acetate, M.P.1931'94.5 C.

(5) 3,3-ethylenedioxy-5i3,IOB-estrane-SJO,17B-triol l7- acetate (9.6parts by weight) is dissolved in a mixture of acetic acid (2000 parts byvolume) and water. (500 parts by volume), warmed for 30 minutes on awater bath,

and evaporated under reduced pressure to produce a crude crystallinesubstance. The substance is subjected. to thinlayer chromatography withether as the developing solvent, and recrystallized from anacetone-hexane mixture to yield 17 3-acetyloxy-5,l0-dihydroxy-5fi,l08-estran- 3-one, M.P. 183185 C. (5.1 parts by weight).

3,3-ethylenedioxy-'5a,l0a-estrane-5,10,17B-triol 17-ace-" tate yields17/8-acetyloxy-5,10-dihydroxy-5a, 10a-estran-3- one, following thepreceding procedure.

(1) 3,3-ethylenedioxy-5(10)-estren-17fi-ol (4.3 parts by weight) isdissolved in anhydrous toluene parts by volume) in nitrogen atmosphere.The resulting solution is refluxed for 150 minutes with portionwiseaddition of sodium hydride (0.8 part by weight) under stirring. To

the solution there is added dropwise'a solution of benzyl bromide (2.8parts by Weight) in anhydrous toluene (8 parts by volume) and the thusobtained mixture is refluxed for minutes. The reaction mixture is, afteraddition of water, extracted with ether. The etheral extract is washedwith aqueous saturated-sodium chloride solution, dried over anhydroussodium sulfate and evaporated under reduced pressure to leave a yellowoil (6.5 parts by weight). The oil is chromatographed over alumina (300parts by weight). The fraction eluted with solvent system hexane-benzeneyields crystalline 3,3-ethylenedioxy- 5(l0)-estren-17fi-ol benzyl ether,M.P. 81.5-83 C. (3.7 parts by weight) after recrystallization fromdilute aqueous ethanol.

(2) 3,3-ethylenedioxy-5(10)-estren-17,B-ol benzyl ether (3 parts byWeight) is dissolved in a mixture of anhydrous benzene (30 parts byvolume) and pyridine (1 part by volume). Osmium tetroxide (2 parts byweight) is added to the solution and the resultant mixture is kept for48 hours at room temperature. The reaction mixture is treated withhydrogen sulfide under cooling with ice and filtered to removeprecipitates. The precipitates are Washed with chloroform. The filtrateand washings are combined, and sequentially washed with water, aqueous1%-acetic acid solution, aqueous 5%-sodium sulfate solution and water,dried over anhydrous sodium sulfate and then evaporated under reducedpressure to leave crude product (3 parts by weight). The product issubjected to thin-layer chromatography using ether as the developingsolvent to separate two adsorption bands, which yield, respectively,3,3-ethylenedioxy 513,105 estrane-5,10,17B- triol 17-benzyl ether, M.P.156l57.5 C. (1.3 parts by weight) and 3,3-ethylenedioxy 5zx,l0ocestrane-5,10,17,8- triol 17-benzyl ether, M.P. 164.5*166 C. (1.6 partsby Weight) through recrystallization from ether.

(3) 3,3-ethylenedioxy-5fl,IOfl-estrane-S,10-17fl-triol 17- benzyl ether(1.6 parts by weight) is dissolved in a mix ture of dioxane (40 parts byvolume) and methanol (50 parts by volume) and catalytically hydrogenatedover 10%-palladised carbon catalyst (0.8 part by weight). The reactionmixture is filtered. The filter cake is washed with chloroform-methanolmixture. The filtrate and washings are combined and evaporated to leavecrude product (1.3 parts by weight). The product is subjected tothin-layer chromatography with the developing solvent systemchloroform-acetone (2:1) and the resultant adsorption band (Rf=0.3) istreated to yield 3,3-ethylenedioxy-5,8,- IOB-estrane-S,10,17/3-tri01(0.9 parts by weight), M.P. 173.5 C., through recrystallization fromether.

3,3 ethylenedioxy 50:,1000-651213115-5,10,1713-t1i0l 17- benzyl ether(1.2 parts by weight) is dissolved in a mixture of dioxane (7 parts byvolume) and methanol (40 parts by volume) and catalytically hydrogenatedover 10%-palladised carbon catalyst (0.6 part by Weight) to yield 3,3ethylenedioxy 5a,10a-estrane-5,10,17,8-triol (0.9 parts by weight), M.P.217222 C.

(4) 3,3-ethylenedioxy-5f3,lOB-estrane-SJO,17/8-triol (1 part by weight)is dissolved in aqueous 70%-acetic acid solution (50 parts by volume)and the resultant solution -is heated for 20 minutes on a Water bath.The reaction mixture is then evaporated under reduced pressure to leavecrude crystalline product (09 part by weight). The product is subjectedto thin-layer chromatography with the solvent system chloroform-acetone(1:1) and treated to obtain 5,10,17B-trihydroxy-5Bl0 8-estran-3-one,M.P. 118120 C. (0.6 part by weight).

Similarly, 3,3-ethylene dioxy5u,10a-estrane-5,l0,175- triol yieldscrystalline 5,10,17/8-trihydroxy-5a,IOa-estran- 3-one, M.P. 158-160 C.

Example 5.Preparati0n 0]" 5,10-dihydr0xy-5BJOB- and 5 0a,] 0a-eslrane-3,1 7 -di0nes 3,3 ethylenedioxy-5(10)-estren-17-one (1.5 parts by weight)is dissolved in anhydrous benzene (30 parts by volume) and then osmiumtetroxide (1.4 parts by weight) is added to the solution. The resultantmixture is allowed to react at room temperature for 73 hours. Thereaction mixture is thereafter treated in a manner described in theExample 2 (3), resulting in a mixture of 3,3-ethylenedioxy-5,10-dihydroxy-5;3,10fland -a,10a-estran-17-ones (1.0 part by weight). Theresultant mixture is chromatographed over alumina (230 parts by weight).The fraction eluted with hexane-benzene (-1:1) yields 3,3-ethylenedioxy5,10 dihydroxy 55,108 estran-17-one, M.P. 180-182 C. (0.6 part byweight) after recrystallization from ether. The following eluates yieldoily 3,3-ethylenedioxy-5,10-dihydroxy-5a,10a-estran-17-one (0.2 part byweight). Each product yields the corresponding deketalation compounde.g. 5,10-dihydroxy-5fi,10j3- or -5a,10aestrane-3,17-dione according toa procedure similar to that described in Example 2 (4).

Example 6.Preparati0n of 17a-methyl-5,10,1 7,B- trihydroxy-S {3,1 0B-estran-3-0ne (1) 3,3 ethylenedioxy-Sfi,10B-estrane-5,10,17p-triol (6.6parts 'by Weight) is oxidized by a mixture of chromium trioxide (10parts by weight) and pyridine (300 parts by volume) at room temperaturefor hours. The reaction mixture is treated thereafter in the mannerdescribed in Example 2 (1) to yield 3,3-ethylenedioxy-5,10- dihydroxy5,8,10,8-estran-17-one, M.P. 180182.5 C. (4.9 parts by weight) afterrecrystallization from ether.

(2) 3,3 ethylenedioxy-S,IO-dihydroxy-SB,10,8-estran- 17-one (1.5 partsby weight) is dissolved in anhydrous benzene (100 parts by volume). Thesolution is added dropwise into a mixture prepared according to thereaction of lithium metal (0.6 part by weight) in anhydrous ether (200parts by volume) and methyl iodide (8 parts by volume) in anhydrousether (100 parts 'by volume). The resultant mixture is then allowed toreact at room temperature for 4 hours with stirring. The reactionmixture is, after adding 2 drops of aqueous 10%-ammonium chloridesolution, extracted with ether. The extract is 'washed with aqueoussodium chloride solution, dried over anhydrous sodium sulfate andevaporated to leave a syrupy substance (1.5 parts by weight). Theproduct is subjected to thin-layer chromatography usingchloroform-methanol (10:1) mixture as the developing solvent system. Theadsorption band of Rf-:0.4 yields3,3-ethylenedioxy-17amethyl-SBJOfl-estrane-S,10,17B-triol, M.P.164-165.5 C. (0.8 part by weight) by recrystallization from methanol.

(3) The resultant product yields the corresponding deketalationcompound, 17a methyl-5,10,17B-trihydroxy- SBJOIi-estran-S-Qne, in amanner similar to that of Example 2 (4).

Example 7.Preparati0n of 3,3-ethylenedioxy-5BJ05- and-5a,10a-estrane-5,10,17fi-triols To a suspension of ruthenium dioxide(7.4 parts by weight: 54.6%-purity) in carbon tetrachloride (600 partsby volume), there is added a solution of sodium periodate (trihydrate)(30.2 parts by Weight) in water (800 parts by volume) with externalice-cooling and stirring, and the resulting mixture is stirred for 50minutes under ice cool ing. The resultant mixture is separated in aseparating funnel to collect the organic layer (ruthenium tetroxidesolution: Tetrahedron, 19, 1961 (1963)). To a solution of3,3-ethy1enedioxy-5(10)-estren-17;9-ol 17-acetate (10 parts by Weight)in carbon tetrachloride (200 parts by volume) at a temperature from to-32 C., the said organic layer (previously cooled to 30 to 32 C.) isadded. A reaction takes place. After 5 minutes the mixture becomes aslurry. Hydrogen sulfide is then passed through the reaction mixture toeliminate the ruthenium ion as precipitates, which are removed byfiltration. The filter cake is Washed with chloroform. The filtrate andwashings are combined, washed with water and treated in the conventionalmanner to yield crude product (10.8 parts by Weight). The product isseparated according to conventional thin-layer chromatography by thedeveloping solvent system chloroform-methanol (40:1) as in the foregoingexamples, thereby yielding 3,3-ethylenedioxy-513,10B-estrane-5,10,17,8-triol 17-acetate, M.P. 166167 C. (5.5 parts byweight) and 3,3 ethylenedioxy-5a,10aestrane-5,10,l7fl-triol 17-acetate,M.P. 196-196.5 C. (4.0 parts by weight), and which are recrystallizedfrom ether.

What is claimed is:

1. A compound of the formula:

group, in which R represents a hydrogen atom, a lower alkyl group, alower alkenyl group or a lower alkynyl group, and R represents ahydrogen atom, a lower alkanoyl group or benzyl group.

2. The compound of claim 1 which is 5,10,175-trihydroxy-5a,10a-estran-3-one.

3. The compound of claim 1 which is 17a-methy1-5,10- 178-trihydroxy-5a,10a-estran-3-one.

4. The compound of claim 1 which is 17B-acetyloxy-5,-10-dihydroxy-5a,10a-estran-3-one.

5. The compound of claim 1 which is 3,3-ethylenedioxy- 5 a,LOa-estrane-S, 10- l7fl-triol.

6. The compound of claim 1 which is 3,3-ethylenedioxy-5a,10u-estrane-5,10,17fl-triol 17-acetate.

7. The compound of claim 1 which is 3,3-ethylenedioxy-17a-methyl-5a,10a-estrane-S,10-17fi-triol.

8. The compound of claim 1 which is 3,3-ethylenedioxy-5a,10a-estrane-5,10,17fi-triol 17-benzyl ether.

References Cited UNITED STATES PATENTS 3,211,719 10/1965 Von Wartburg etal. 260-2105 OTHER REFERENCES Cross et al., J. Org. Chem., 29, 2195-2200(1964). Noller, Chemistry of Organic Compounds, 3rd ed. Philadelphia, W.B. Saunders Co. (1965), p. 816.

LEWIS GOTTS, Primary Examiner.

T. M. MESHBESHER, Assistant Examiner.

